Many physiological factors influence both the gastrointestinal transit time and the release of a drug from a controlled release dosage form and thus the uptake of the drug into the systemic circulation. Dosage forms should therefore be designed so that such variable factors do not compromise the efficacy and safety of the product.
In humans, a reproducible gastrointestinal transit time of a depot formulation can be achieved only by a controlled release multiple-units dosage form.
The term "controlled release multiple-units formulation" (Bechgaard & Hegermann Nielsen, 1978) indicates a pharmaceutical formulation comprising a multiplicity (typically at least 100) of individual coated (or "microencapsulated") units contained in the formulation in such a form that the individual units will be made available from the formulation upon disintegration of the formulation in the stomach of animals, including humans, who have ingested the formulation. Typically, the multiple-units formulation may be a capsule which disintegrates in the stomach to make available a multiplicity of individual coated units contained in the capsule, or a tablet which disintegrates in the stomach to make available a multiplicity of coated units originally combined in the tablet.
Drug release from a controlled release dosage form is generally controlled either by diffusion through a coating or by erosion of a coating by a process dependent on, e.g., enzymes or pH. The importance of a pH independent diffusion with respect to obtaining a reproducible rate of availability and to minimizing intra- and intersubject variations is known (GB Patent No. 1 468 172 and Bechgaard & Baggesen, 1980). It is also known that controlled drug release in vivo can be achieved through an erodable process by enteric coating of a multiple-units dosage form (Green, 1966; McDonald et al., 1977; Bogentoft et al., 1978).
Both above-mentioned types of controlled release multiple-units formulation techniques aim at a controlled release of active substance in a predetermined pattern to reduce and delay the peak plasma concentration without affecting the extent of drug availability. Due to a lower peak plasma concentration, the frequency of undesirable sideeffects may be reduced, and due to the delay in the time it takes to obtain the peak plasma concentration and the prolongation of the time at the therapeutically active plasma concentration, the dosage frequency may be reduced to a dosage taken only twice or once a day, in order to improve patient compliance.
A further advantage of the controlled release multiple-units dosage form is that high local concentrations of the active substance in the gastrointestinal system is avoided, due to the units being distributed freely throughout the gastrointestinal tract, independent of gastric emptying. If the mucosa of the stomach is more sensitive to the active substance than the intestinal mucosa, controlled release formulations avoiding release of active substance in the gastric area will be preferred; formulations of this type are controlled release multiple-units formulations in which the coatings are substantially resistant to gastric conditions.
The present invention deals with multiple-units dosage forms which are diffusion-coated.
In the known art preparations of diffusion-coated controlled release multiple-units formulations, diffusion film-coating mixtures have been used which contain synthetic film-forming agents dissolved or dispersed in organic solvents, e.g. isopropanol, ethanol, acetone, or mixtures thereof. However, although these mixtures show advantages in that the film-forming agents are diffusion controlling per se, that is, without any modification or addition, and the film formed is nontacky, they suffer from serious disadvantages from an environmental and process-economic point of view:
The use of organic solvents gives rise to environmental pollution, danger of explosion, and health hazards unless costly recycling procedures are used, such as recycling in scrubber towers, and the fact that the film coating mixtures have a low dry matter content (normally less than 15% by weight), incurs long processing periods resulting in a low process efficiency.
From an environmental and process-economic point of view, water-based film-coating mixtures are more desirable; the present invention concerns developments relating to water-based film coatings.